Li Jie-Ning, Loh Zhu-Jun, Chen Hui-Wen, Lee I-Ying, Tsai Jui-Hung, Chen Pai-Sheng
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Breast Medical Center, National Cheng Kung University Hospital, Tainan, Taiwan; Research Center for Medical Laboratory Biotechnology, National Cheng Kung University, Tainan, Taiwan.
Breast Medical Center, National Cheng Kung University Hospital, Tainan, Taiwan; Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Transl Oncol. 2024 Oct;48:102062. doi: 10.1016/j.tranon.2024.102062. Epub 2024 Aug 1.
Breast cancer remains the most prevalent cancer in women globally, posing significant challenges in treatment due to the inevitable development of resistance to targeted therapies like everolimus, an mTOR inhibitor. While several mechanisms of resistance have been proposed, the role of snoRNAs in this context remains inadequately explored. Our study unveils a novel connection between snoRNAs and everolimus resistance, focusing on the snoRNA U50A. We discovered that U50A negatively regulates mTOR signaling by transcriptionally downregulating mTOR gene expression, which consequently leads to decreased sensitivity to everolimus treatment. Through RNA sequencing, gene set enrichment analyses, and experimental validations, we established that U50A overexpression in breast cancer cells results in mTOR downregulation and subsequently, everolimus desensitization. Clinical results further supported our findings, showing a higher prevalence of everolimus resistance in tumors with elevated U50A expression. Moreover, our results suggest that U50A's effect on mTOR is mediated through the suppression of the transcription factors c-Myc, with a notable impact on cancer cell viability under everolimus treatment. This study not only highlights the complex role of snoRNAs in cancer drug resistance but also proposes U50A as a potential biomarker for predicting everolimus efficacy in breast cancer treatment.
乳腺癌仍然是全球女性中最常见的癌症，由于对依维莫司（一种mTOR抑制剂）等靶向治疗药物不可避免地产生耐药性，在治疗方面带来了重大挑战。虽然已经提出了几种耐药机制，但在此背景下snoRNA的作用仍未得到充分探索。我们的研究揭示了snoRNA与依维莫司耐药性之间的一种新联系，重点关注snoRNA U50A。我们发现，U50A通过转录下调mTOR基因表达来负向调节mTOR信号通路，从而导致对依维莫司治疗的敏感性降低。通过RNA测序、基因集富集分析和实验验证，我们确定乳腺癌细胞中U50A的过表达会导致mTOR下调，进而导致对依维莫司脱敏。临床结果进一步支持了我们的发现，显示U50A表达升高的肿瘤中依维莫司耐药的发生率更高。此外，我们的结果表明，U50A对mTOR的影响是通过抑制转录因子c-Myc介导的，对依维莫司治疗下的癌细胞活力有显著影响。这项研究不仅突出了snoRNA在癌症耐药性中的复杂作用，还提出U50A作为预测依维莫司在乳腺癌治疗中疗效的潜在生物标志物。
